Elevated levels of circulating cell-free DNA and neutrophil proteins are associated with neonatal sepsis and necrotizing enterocolitis in immature mice, pigs and infants
Elevated levels of circulating cell-free DNA and neutrophil proteins are associated with neonatal sepsis and necrotizing enterocolitis in immature mice, pigs and infants
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DOI：
10.1177/1753425917719995
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发表时间：
2017-08-01
期刊：
影响因子：
3.2
通讯作者：
Sangild, Per T.
中科院分区：
文献类型：
--
作者：
Duc Ninh Nguyen;Stensballe, Allan;Sangild, Per T.
早产儿易患晚发性脓毒症(LOS)和坏死性小肠结肠炎(NEC)，但疾病发病机制和特异性诊断标记物缺乏。循环中的游离细胞DNA(CfDNA)和免疫细胞衍生蛋白参与了成人的多种免疫疾病，但尚未在早产儿中进行研究。我们探讨了循环中性粒细胞相关蛋白和cfDNA与LOS和/或NEC的关系。使用临床相关的早产猪自发LOS和NEC发育模型，我们研究了血浆中性粒细胞相关蛋白和cfDNA，以及肠道组织中的细胞因子。进一步研究了早产猪和新生败血症小鼠以及早产儿是否有LOS和/或NEC的cfDNA水平的变化。114头早产猪中有15头自发发展为LOS和NEC，在全身炎症期间，它们的肠道IL-6和IL-1水平以及血浆cfDNA、中性粒细胞相关蛋白和参与血小板-中性粒细胞相互作用的蛋白水平升高。中性粒细胞相关蛋白的丰度与cfDNA水平高度相关。此外，新生小鼠和早产猪对表皮葡萄球菌的攻击增加了血浆cfDNA水平和脾中细菌的积累。在婴儿中，血浆cfDNA水平在LOS诊断时和NEC前1-6d升高。总之，血浆cfDNA和中性粒细胞蛋白水平升高与LOS和NEC的诊断有关。
Preterm infants are highly susceptible to late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), but disease pathogenesis and specific diagnostic markers are lacking. Circulating cell-free DNA (cfDNA) and immune cell-derived proteins are involved in multiple immune diseases in adults but have not been investigated in preterm neonates. We explored the relation of circulating neutrophil-associated proteins and cfDNA to LOS and/or NEC. Using a clinically relevant preterm pig model of spontaneous LOS and NEC development, we investigated neutrophil-associated proteins and cfDNA in plasma, together with cytokines in gut tissues. The changes in cfDNA levels were further studied in preterm pigs and neonatal mice with induced sepsis, and in preterm infants with or without LOS and/or NEC. Fifteen of 114 preterm pigs spontaneously developed both LOS and NEC, and they showed increased intestinal levels of IL-6 and IL-1 and plasma levels of cfDNA, neutrophil-associated proteins, and proteins involved in platelet-neutrophil interaction during systemic inflammation. The abundance of neutrophil-associated proteins highly correlated with cfDNA levels. Further, Staphylococcus epidermidis challenge of neonatal mice and preterm pigs increased plasma cfDNA levels and bacterial accumulation in the spleen. In infants, plasma cfDNA levels were elevated at LOS diagnosis and 1-6d before NEC. In conclusion, elevated levels of plasma cfDNA and neutrophil proteins are associated with LOS and NEC diagnosis.